The goal of this project is to determine the metabolic fate of the thyroid hormones, including overall disposal rates, mechanisms for uptake by tissues, binding to tissue components including receptors, and metabolic transformations. Special emphasis will be placed on study of certain organic anions (bilirubin, indocyanine green, cholecystographic agents), shown in preliminary studies to inhibit hepatic uptake of thyroid hormones. By incubating tissue slices from rat liver, kidney, thyroid and other organs with labeled thyroxine, triiodothyronine, and other iodothyronines, rates of uptake and of conversion to labeled metabolites will be determined, and the effects thereon of metabolic inhibitors, drugs, and other hormones assessed. Broken cell preparations and particulate cell fractions will be employed to define the kinetics of iodothyronine-metabolizing enzyme activities, binding sites for iodothyronines, and the mode of action of inhibitors. Radioimmunoassay for metabolites will be employed to confirm radioactive tracer results. Important findings in vitro will, when possible, be tested in vivo, using laboratory animals. The focus of the people is toward human physiology and pathophysiology; therefore hormone turnover studies will be performed in human subjects, to define the effects of certain diseases and drugs on metabolic clearance rates, specific tissue uptakes, and biotransformations of the thyroid hormones. Also, iodothyronine metabolism will be assessed in certain human tissues in vitro, especially normal and abnormal thyroid glands when tissue becomes available at surgery.